Obesity Contributes to Transformation of Myometrial Stem-Cell Niche to Leiomyoma via Inducing Oxidative Stress, DNA Damage, Proliferation, and Extracellular Matrix Deposition

Leiomyomas (fibroids) are monoclonal tumors in which myometrial stem cells (MSCs) turn tumorigenic after mutation, abnormal methylation, or aberrant signaling. Several factors contribute to metabolic dysfunction obesity, including cellular proliferation, oxidative stress, and DNA damage. The present study aims determine how adipocytes adipocyte-secreted affect changes MSCs a manner that promotes the growth of uterine leiomyomas. Myometrial were isolated from uteri patients by fluorescence-activated cell sorting (FACS) using CD44/Stro1 antibodies. Enzyme-linked immunosorbent assay (ELISA), Western blot, immunocytochemistry assays performed on human (SW872) co-cultured with treated leptin adiponectin examine effects extracellular matrix (ECM) deposition, damage, Co-culture SW872 increased MSC proliferation compared culture alone, according 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) results. expressions PCNA COL1A significantly co-culture. In addition, expression these markers was treatment decreased MSCs. Wnt/β-catenin TGF-β/SMAD signaling pathways promote ECM deposition Wnt4, β-catenin, TGFβ3, pSMAD2/3 when adipocytes. We found co-culture resulted NOX4 expression, reactive oxygen species production, γ-H2AX expression. Leptin acts binding its receptor (LEP-R), leading signal transduction, resulting transcription genes involved angiogenesis, glycolysis. MSCs, LEP-R, pSTAT3/STAT3, pERK1/2/ERK/12. Based above results, we suggest obesity may mediate initiation tumorigenesis,